Phase 2 Evaluation of Isatuximab, Pomalidomide, and Dexamethasone in Relapsed Multiple Myeloma Post-Lenalidomide and Proteasome Inhibitor Therapy

Trial ID: 2024-516060-28-00
Protocol: EAE 115
Sponsor: Hellenic Society Of Hematology

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Diseases & Conditions

Plasma cell myeloma

Objectives

The primary objective of this Phase 2 study is to evaluate the effect of **isatuximab** in combination with pomalidomide and low-dose dexamethasone on the 6-month overall response rate (ORR) in patients with **multiple myeloma** who are experiencing their first relapse after receiving one prior line of therapy that included lenalidomide and a proteasome inhibitor. This is clinically relevant as it aims to determine the efficacy of this combination therapy in improving response rates in a specific patient population, potentially offering a new therapeutic option for those with limited treatment history.

Secondary objectives include evaluating the effect of isatuximab in combination with pomalidomide and low-dose dexamethasone on:

Progression-Free Survival (PFS)
Overall Survival (OS)
Minimal Residual Disease (MRD) negativity rate
Time to Response (TTR)
Duration of Response (DoR)
Safety
Exploratory: The effect on PFS of patients who attained ≥ very good partial response (VGPR) after six cycles of treatment with isatuximab Q2W plus pomalidomide/low-dose dexamethasone

Participants

The clinical trial involves **patients** diagnosed with **multiple myeloma** who have previously undergone one line of therapy that included lenalidomide and a proteasome inhibitor. The study population comprises both male and female participants aged 18 years and older. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on their medical history, specifically those who have relapsed for the first time after receiving the specified prior treatment. The trial includes individuals with adequate bone marrow and hepatic function, as well as those with a documented diagnosis of multiple myeloma and current evidence of measurable disease. Participants are required to have an Eastern Cooperative Oncology Group Performance Status of 2 or less. The study population includes a vulnerable population, indicating that additional ethical considerations are in place to protect these individuals. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **isatuximab** in combination with **pomalidomide** and **dexamethasone** in patients with **multiple myeloma** who have received one prior line of therapy containing lenalidomide and a proteasome inhibitor. This is a Phase 2, randomized, double-blind, controlled study. The trial aims to assess the 6-month overall response rate (ORR) as the primary endpoint, with secondary endpoints including progression-free survival (PFS), overall survival (OS), minimal residual disease (MRD) negativity, time to response (TTR), and duration of response (DoR). Safety will be monitored through the incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs).

The trial is expected to last until October 31, 2026, with recruitment having started on May 31, 2022. Participants will be involved in the study for a maximum treatment period of 42 days, with the possibility of early termination if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor response and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have signed an informed consent form, be 18 years or older, and have received only one prior line of anti-myeloma therapy. Exclusion criteria are not specified in the provided data.

Study visits are structured to ensure comprehensive monitoring and data collection. The screening visit will involve assessments to confirm the diagnosis of multiple myeloma and the presence of measurable disease. Follow-up visits will occur at regular intervals to evaluate treatment efficacy and monitor for any adverse effects. The end-of-study visit will include a final assessment of the primary and secondary endpoints. Participants may be withdrawn from the study if they do not adhere to the protocol, experience significant adverse effects, or if the investigator deems it necessary for their safety.

Treatment

The clinical trial involves the administration of **POMALIDOMIDE**, an immunomodulatory agent, as part of the treatment regimen. **POMALIDOMIDE** is provided in the form of a hard capsule and is administered orally. The dosing schedule is determined based on the study protocol, with a maximum treatment period of 42 days. The specific dosage in milligrams is not detailed in the provided data. Compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the protocol.

**DEXAMETHASONE** is utilized as a non-experimental treatment in this study. It is available in two pharmaceutical forms: an oral solution and a solution for injection/infusion. The oral solution is administered orally, while the solution for injection/infusion is administered intravenously. The dosing schedule and frequency are aligned with standard clinical practices for the management of multiple myeloma, although specific dosage details are not provided in the data. Participant compliance with **DEXAMETHASONE** administration is monitored to ensure protocol adherence.

**ISATUXIMAB** is another key component of the treatment regimen, provided as a concentrate for solution for infusion. It is administered intravenously, with the dosing expressed in milligrams per kilogram of body weight. The maximum treatment period is 42 days, and the product is specifically packaged and labeled for clinical trial use. Compliance with the administration schedule is closely monitored to ensure accurate dosing and adherence to the study protocol.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the **Overall Response Rate (ORR)** at six months of treatment with isatuximab in combination with pomalidomide and low-dose dexamethasone. ORR is defined as the proportion of patients achieving stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR), as evaluated by the investigator using the International Myeloma Working Group (IMWG) response criteria.

Secondary efficacy endpoints include **Progression-Free Survival (PFS)**, which is the time from study treatment initiation to the first documentation of progressive disease (PD), death from any cause, initiation of further anti-myeloma treatment, or data cut-off, whichever occurs first. **Overall Survival (OS)** will be measured from the start of treatment to the day of death from any cause. **Minimal Residual Disease (MRD) negativity** will be assessed at suspected CR, and **Time to Response (TTR)** will be calculated from treatment initiation to the first objective response of PR or better. **Duration of Response (DoR)** is defined as the time from the first response to the first PD or death, applicable to patients achieving PR or better.

Safety assessments will include the incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs), recorded continuously from informed consent until 30 days post-treatment. AEs and laboratory parameters will be graded using the NCI-CTCAE version 5.0. Specific safety laboratory tests are planned in case of infusion reactions, with full details provided in the study protocol.

Inclusion and Exclusion Criteria

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Inclusion Criteria

1.Patient has signed an informed consent form (ICF) indicating that he or she understands the purpose of the procedures required for the study and is willing to participate in the study. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol, as referenced in the ICF
2.Male or female patients aged 18 years or older at the time of the ICF signature
3.Patients who have received ONLY one prior line of anti-myeloma therapy, which included lenalidomide (at least 2 cycles, either alone or in combination) and a proteasome inhibitor (e.g. bortezomib, carfilzomib, ixazomib). Patients must have achieved at least a response of MR or better based on the investigator's determination of response as defined by the IMWG criteria. Note 1: An induction treatment followed by ASCT and consolidation/maintenance will be considered as one line of treatment. Note 2: The number of prior lines will be defined according to the guidelines for determination of the number of prior lines of therapy in multiple myeloma (Appendix F)
4.Patients with a documented diagnosis of MM and with current evidence of measurable disease defined as: -Serum monoclonal protein (M-protein) level ≥0.5 g/dL, measured using serum protein electrophoresis (SPEP) and/or -Urine M-protein level ≥200 mg/24 hours, measured using urine protein electrophoresis (UPEP), or -Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio
5.Patients must have documented evidence of PD, based on the investigator's determination of response as defined by the IMWG criteria, on or after the last line of treatment
6.Adequate bone marrow and hepatic function as defined by ALL the laboratory criteria : -Absolute Neutrophil Count (ANC) ≥1.0 x 109/L; GCSF administration is not allowed to reach this level -Hemoglobin level ≥7.5 g/dL (≥4.65 mmol/L); -Platelet count ≥75 x 109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells OR Platelet count ≥50 x 109/L in patients in whom ≥50% of bone marrow nucleated cells are plasma cells; [transfusions are not permitted to reach this level] -Alanine aminotransferase (ALT) level ≤2.5 x ULN -Aspartate aminotransferase (AST) level ≤2.5 x ULN -Total bilirubin level ≤1.5 x ULN (except for Gilbert Syndrome: direct bilirubin ≤1.5 x ULN) -Creatinine clearance ≥30 mL/min; calculated using Cockcroft Gault -Serum calcium corrected for albumin ≤14.0 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤ 6.5 mg/dL (≤1.6 mmol/L)
7.Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2 (see Appendix B)
8.For patients experiencing toxicities resulting from previous therapy, the toxicities must be resolved or stabilized to ≤ Grade 1

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Exclusion Criteria

1.Previous therapy with any anti-CD38 monoclonal antibody within 12 months before C1D1
2.Previous exposure to pomalidomide
3.Patient has received anti-myeloma treatment within two weeks or five pharmacokinetic half-lives of the treatment, whichever is longer, before Cycle 1, Day 1. The only exception is emergency use of a short course of corticosteroids (the equivalent of dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before C1D1
4.Previous allogeneic stem cell transplant or autologous stem cell transplantation (ASCT) within 12 weeks before C1D1
5.History of malignancy (other than MM) within three years before C1D1
6.Clinical signs of meningeal involvement of MM
7.Clinically significant cardiac disease, including: a) Myocardial infarction within six months before C1D1, or unstable or uncontrolled condition (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV). b) Cardiac arrhythmia (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or higher) or clinically significant electrocardiogram (ECG) abnormalities. c) Electrocardiogram showing a baseline QT interval as corrected QTc >470 msec
8.Known: a) Active hepatitis A b) To be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Patients with resolved infection must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. c) To be seropositive for hepatitis C
9.Known to be seropositive for human immunodeficiency virus (defined by positive testing for human immunodeficiency virus (HIV) antibodies)
10.Gastrointestinal disease that may significantly alter the absorption of pomalidomide
11.Patient has plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis
12.Any concurrent medical or psychiatric condition or disease that is likely to interfere with the study procedures or results or that, in the opinion of the investigator, would constitute a hazard for participating in this study
13.Ongoing ≥Grade 2 peripheral neuropathy
14.Patient had ≥Grade 3 rash during prior therapy
15.Patient has had major surgery within two weeks before C1D1, or has not fully recovered from an earlier surgery, or has a surgery planned during the time the patient is expected to participate in the study or within two weeks after the last dose of study drug administration. Note: patients with planned surgical procedures to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery
16.Patient has known allergies, hypersensitivity, or intolerance to any of the study drugs, monoclonal antibodies, human proteins, or their excipients (refer to isatuximab IB) or known sensitivity to mammalianderived products
17.Patient was vaccinated with live vaccines within four weeks prior to C1D1
18.Pregnant or nursing women
19.a. Females of childbearing potential (FCBP) unwilling to prevent pregnancy with the use of two reliable methods of contraception for ≥4 weeks before the start of study treatment, during treatment (including dose interruptions), and up to five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, injections, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). b. FCBP who are unwilling or unable to be tested for pregnancy: a) before study treatment initiation, b) weekly during 1st month of treatment and then prior to each treatment cycle administration or c) every two weeks in case of irregular menstrual cycles, and d) up to five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer
20.Male participants who refuse to practice true abstinence or use a condom during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions and at least five months following the last dose of isatuximab or three months following the last dose of the rest of the study treatment, whichever is longer, even if he has undergone a successful vasectomy

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Greece	Not Recruiting	31 May 2022	56

Sites & Investigators

Research sites

General University Hospital Of Larissa Metaxa Cancer Center Hospital Of Piraeus Theageneio Cancer Hospital University General Hospital Of Ioannina

Investigators

Emmanouil S.Alexandros S.Anastasia S.Sosana D.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Treatment Duration	EU MP Number
Isatuximab	Test	SOLUTION FOR INFUSION	INTRAVENOUS USE	42	PRD10653334
DEXAMETHASONE	Test	—	INTRAVENOUS USE	42	SUB07017MIG
POMALIDOMIDE	Test	—	ORAL USE	42	SUB33379
POMALIDOMIDE	Test	—	ORAL USE	42	SUB33379
POMALIDOMIDE	Test	—	ORAL USE	42	SUB33379
POMALIDOMIDE	Test	—	ORAL USE	42	SUB33379
DEXAMETHASONE	Test	—	ORAL USE	42	SUB07017MIG
Isatuximab	Test	SOLUTION FOR INFUSION	INTRAVENOUS USE	42	PRD10652636